Cortical Neurogenesis Requires Bcl6-Mediated Transcriptional Repression of Multiple Self-Renewal-Promoting Extrinsic Pathways
Cortical Neurogenesis Requires Bcl6-Mediated Transcriptional Repression of Multiple Self-Renewal-Promoting Extrinsic Pathways
复制标题
DOI：
10.1016/j.neuron.2019.06.027
复制
发表时间：
2019-09-25
期刊：
影响因子：
16.2
通讯作者：
Vanderhaeghen, Pierre
中科院分区：
文献类型：
--
作者：
Bonnefont, Jerome;Tiberi, Luca;Vanderhaeghen, Pierre
在神经发生过程中，祖细胞通过内在和外在线索的相互作用从自我更新转变为分化，但这些线索是如何整合的仍然知之甚少。在这里，我们结合联合收割机全基因组转录和表观遗传分析与体内功能的研究，以证明Bcl 6，转录抑制剂以前报道，以促进皮层神经发生，作为一个驱动程序的神经性转变，通过直接沉默的选择性剧目的基因属于多个外在途径，促进自我更新，最引人注目的Wnt途径。在分子水平上，Bcl 6通过Sirt1募集，然后通过组蛋白去乙酰化来抑制其靶点。我们的数据确定了一种分子逻辑，通过这种逻辑，单个细胞内在因子抑制有利于自我更新的多种外在途径，从而确保神经元命运转变的稳健性。
During neurogenesis, progenitors switch from self-renewal to differentiation through the interplay of intrinsic and extrinsic cues, but how these are integrated remains poorly understood. Here, we combine whole-genome transcriptional and epigenetic analyses with in vivo functional studies to demonstrate that Bcl6, a transcriptional repressor previously reported to promote cortical neurogenesis, acts as a driver of the neurogenic transition through direct silencing of a selective repertoire of genes belonging to multiple extrinsic pathways promoting self-renewal, most strikingly the Wnt pathway. At the molecular level, Bcl6 represses its targets through Sirt1 recruitment followed by histone deacetylation. Our data identify a molecular logic by which a single cell-intrinsic factor represses multiple extrinsic pathways that favor self-renewal, thereby ensuring robustness of neuronal fate transition.